The interplay between cognition, functional and dual-task gait in persons with a vestibular disorder versus healthy controls

Close links exist between vestibular function and cognition. Dual-task (DT) tests may have ecological validity to assess the impact of daily life cognitive-motor demands in people with vestibular dysfunction (PwVD), functional gait and falls risk. The present paper aimed at building predictive models for functional gait under DT conditions, while clarifying the impact of vestibular dysfunction, individual characteristics, varying task types and motor-cognitive demands. Case-controlled observational study with 39 PwVD and 62 healthy participants. The Functional Gait Assessment (FGA), with and without an additional motor, numeracy, or literacy task, was completed. Multiple linear regression was used to fit models to predict FGA under single and DT performance. Dual task cost (DTC, %) was calculated to assess DT interference on FGA performance using the equation: 100*(single task score–dual task score)/single-task score. Following Bonferroni corrections for multiple comparisons (corrected alpha level of 0.003), PwVD had poorer performance than controls for all FGA conditions (p < 0.001), motor (− 3.94%; p = 0.002) and numeracy (− 22.77%; p = 0.001) DTCs and spatial working memory (p = 0.002). The literacy DTC was marginally significant (− 19.39% p = 0.005). FGA single and DT motor, numeracy, and literacy models explained 76%, 76%, 66% and 67% of the variance respectively for PwVD. Sustained attention, visual memory and sex contributed to all models; short-term visual recognition memory, balance confidence, and migraine contributed to some models. Cognitive performance is impaired in PwVD. Motor, numeracy and literacy tasks impair functional gait performance. Cognitive assessment and FGA with a numeracy or literacy cognitive component should be included within assessment protocols and considered in the provision of targeted interventions for PwVD.


Participants.
Between 2016 and 2019, PwVD were recruited from neuro-otology clinics at the National Hospital for Neurology and Neurosurgery, Queen Square UK, after a complete neurological and neuro-otological examination, including Hallpike positional testing, pure-tone air-conduction and bone conduction threshold audiometry with and without masking, electronystagmography, and caloric testing. In persons with recurrent headaches, migraine was diagnosed according to the International Headache Society International Classification of Headache Disorders 3rd edition diagnostic criteria 22 ; vestibular migraine (VM) was diagnosed if symptoms fit Bárány society criteria 23 . Inclusion criteria were (1) clinical diagnosis of a peripheral vestibular disorder, (2) chronic dizziness and/or unsteadiness, (3) age 18 to 80 years old, and (4) no completion of a vestibular rehabilitation program. Patients with (1) central nervous system involvement, excluding migraine diagnosed as per the International Headache Society International Classification of Headache Disorders 3rd edition diagnostic criteria 22 ; (2) fluctuating symptoms, for example, active Ménière's disease; and (3) blindness; (4) severe or profound hearing loss in the better hearing ear (i.e., average of pure tone hearing threshold levels at 250, 500, 1000, 2000 and 4000 Hz that exceeds 71 decibels hearing level) and (5) orthopedic deficit affecting balance and gait were excluded. Patients with severe migraine (> 3 migraine headaches monthly) or severe depression (Hospital Anxiety and Depression (HADS) score ≥ 15/21 24 ) were also excluded.
Independently mobile, healthy participants, aged 18-80 years old, were recruited via posters placed in local community centers and circular university email to staff and students. Exclusion criteria, chosen due to their potential impact on FGA and/or cognitive test performance, included previous diagnosis of a neurological or vestibular disorder, hearing loss, migraine, cognitive impairment and/or orthopedic/musculoskeletal disorder affecting balance and/or gait.
Outcome measures. The primary outcome to be predicted was the FGA 20 total score which assesses performance on complex gait tasks (i.e. walking with changes in speed, head turns or stepping over obstacles). The FGA total score ranges from 0 to 30 with higher scores indicating better performance. It has shown to be reliable and valid for use in PwVD 20 . Secondary outcomes to be predicted were the FGA DT conditions. The FGA assessment was completed four times in total for each participant: in isolation (FGA single) and while simultaneously performing a motor (FGA-M), literacy (FGA-L) or numeracy (FGA-N) task. The original FGA was always completed first, followed by the DT FGA in computer generated random order (www. rando mizer. org). The FGA-M was performed using the dominant hand to hold a half full cup of water with the elbow flexed at 90°. The cognitive FGA-N DT involved a. counting backwards from 100 in 7's, b. reciting the 8-multiplication table and c. reciting 7 division tables. The cognitive FGA-L DT involved reciting alternate a. alphabet letters, b. days in a week and c. months in a year. Participants performed the cognitive DTs in the order of a → b → c → a. When repeating the same task, participants started from the number, alphabet, day, or month where they finished the previous time.
Statistical analysis. IBM SPSS version 26 (IBM Corp, Armonk, New York, USA) was used for statistical analysis. All data are presented as mean ± SD and median and interquartile range. The data was analyzed using a variety of statistical tests and techniques. First, the chi-square test and Mann-Whitney U test were performed to examine how demographic information differed between the study groups. To test the normality of the distribution for variables, the Shapiro-Wilk test, histogram, and Q-Q plots were used. The results indicated that the data was not normally distributed, therefore, the Mann-Whitney non-parametric test was selected to compare variables between study groups. The effect size was calculated for the Mann-Whitney U test, the standardized test statistic z is divided by the square root of the number of pairs (n). In addition, multiple comparisons can increase the likelihood of Type I errors 38 , and therefore, it is important to adjust p-values to control for such errors. In this study, 19 Mann-Whitney U tests were conducted on a single group variable. To account for multiple comparisons, a Bonferroni correction was applied. The corrected alpha level was calculated by dividing the desired overall alpha level (0.05) by the number of tests performed (19), resulting in a new corrected alpha level of 0.003.
Within-group DTC differences were assessed using Wilcoxon signed-rank test. Spearman's correlation assessed for relationships between cognitive performance, self-report measures and demographic variables (age and sex for both groups and migraine history and hearing loss only for PwVD). www.nature.com/scientificreports/ The dual task cost (DTC) was calculated to assess DT interference. DTC is the percentage change in FGA performance due to the DT condition and was calculated separately for FGA-M, FGA-N and FGA-L using the following equation 39 : In the current study, a more negative DTC indicates a higher impact of adding a secondary task on the primary task (FGA), as a higher FGA score is better. The DTC was only calculated for the primary motor task (FGA), but not for secondary numeracy and literacy task performance as baseline performance on these tasks was not collected.
Predictive models were developed under a multiple linear regression modelling framework as outcomes were continuous. A backwards selection approach was applied to a full model including all potentially relevant predictors that met assumption criteria to derive FGA single and DT performance models. Assumption criteria were (a) independence of residuals (Durbin Watson test values 1.5-2.5/4); (b) linearity, assessed by partial regression plots and a studentized residuals against predicted values plot; (c) homoscedasticity, assessed by visual inspection of a studentized residuals versus unstandardized predicted values plot; (d) no multicollinearity assessed by tolerance values > 0.1 and no correlations between predictors > 0.7; (e) no significant outliers, assessed by checking for studentized deleted residuals > ± 3 SD, leverage values > 0.2, and values for Cook's distance > 1; and (f) assumption of normality was met, assessed by a Q-Q Plot 40 . If highly correlated predictors were identified, only one was included in the multivariable modelling; outliers were filtered out of the data set and the multiple regression analysis was re-run. Model performance was evaluated by calculating adjusted R 2 . Significance level was set at 0.05.
Regression coefficients and standard errors are in Tables 4 and 5 for healthy participants and PwVD, respectively.

Discussion
This study investigated the effect of motor and cognitive DTs on complex gait performance, as assessed by FGA, in both PwVD and healthy participants. All PwVD had chronic symptoms and our findings are only applicable to this population. Results showed more pronounced FGA DTCs for cognitive (numeracy and language) versus motor tasks in both groups. Rapid visual processing, paired associates learning, and gender were predictors of FGA performance under both single and DT conditions in PwVD.
Cognitive function in PwVD and its association with functional gait. Impaired spatial working memory was noted for PwVD compared to healthy participants, which is in agreement with findings reported in previous work in persons with unilateral vestibular loss 41 . Our finding of impaired paired associates learning in PwVD compared to healthy participants was no longer significant following Bonferroni correction. This may be due to under powering of the study. Worse performance for paired associated learning in PwVD is reported in the animal literature; rats use self-motion (vestibular) signals to disambiguate between spatial locations to form object-place associations 42 . The pathway involved may include the medial temporal lobe, which is responsible for the visually induced self-perception of motion 43 and is activated by sensory conflict between visual and vestibular stimuli 44 . Interestingly, bilateral vestibular deafferentation leads to changes in the biogenic amine pathways (serotonin/tryptophan) of the medial temporal lobe 45 . It is an intriguing question whether worse paired associates learning scores in PwVD versus healthy participants may be part of vestibular sensory driven cognitive decline, but both the presence of worse learning scores in PwVD and such a potential association would need to be further investigated. Paired associates learning also predicted all FGA single and DT conditions in PwVD and FGA-L in healthy participants possibly because both gait and an object-space association memory task are dependent on self-motion vestibular (idiothetic) perception 42 .
Given the predictive role of specific cognitive domains for FGA single and DT scores, an area of potentially fruitful research would be studying whether vestibular rehabilitation has positive cognitive effects. In older adults, physical combined with cognitive training resulted in a greater improvement for paired associates learning versus cognitive training alone 46 . Vestibular rehabilitation incorporating progressively more challenging functional gait exercises could lead to improved paired associates learning by promoting enhanced perception of self-motion during locomotion and even by possible direct medial temporal lobe activation 47 . Recently, two exploratory studies assessed vestibular rehabilitation outcomes, in isolation or with the use of a virtual reality head mounted display, in older adults with and without MCI (mild cognitive impairment) and unilateral vestibular hypofunction 48,49 . The findings suggest that people with MCI benefit from vestibular rehabilitation, with improvements noted in functional gait, postural sway, self-perceived handicap from dizziness and/or quality of life. It appears that vestibular hypofunction is more prevalent in older adults with Alzheimer's Disease 50 . Klatt et al. 51 state that vestibular rehabilitation might be able to improve balance, and decrease falls, health care costs, and caregiver burden for people with cognitive impairment and have proposed a theoretical and practical guide for vestibular rehabilitation in this population.
Rapid information processing was identified as a predictor for all FGA single and DT models in PwVD while reaction time was not. Reaction time is a simple visual task response latency, while rapid visual information processing is the response speed for detecting a target number sequence. The reaction time task is reliant on dopamine pathways as the dopamine 4 receptor gene and a DRD4 polymorphism is associated with attentional disorders 52 , while rapid visual information processing is reliant on the cholinergic pathway 53 .
Current findings for PwVD indicate that dynamic gait +/− dual tasking is more "effortful" for this population 1 . Paired associates learning and rapid visual information processing which are related to perception and sensory stimuli predicted FGA single and all DT conditions. These changes in cognitive domains may delay PwVD's ability to encode and embed new information in memory during tasks that require a less practiced task strategy, thus having a negative impact on FGA and DT performance.
In healthy participants, spatial working memory and reaction time predicted FGA single and FGA-N. A small association has previously been observed between gait and spatial working memory 54 while processing speed has been shown to contribute to stepping errors 55 and stride length 56 in older adults. In our study, the predictive role of these cognitive domains is present irrespective of age. However, predictive model effect sizes were weak for healthy participants and results must be considered with caution.
The relationship between FGA scores, age, and sex. Increasing age is associated with poorer FGA performance in healthy adults 28 . The weak predictive role for age in healthy participants is likely due to the predominantly younger age of these individuals in the current versus previous studies 28,57 . Age predicated FGA single and the FGA motor DT condition with older adults having worse scores in PwVD; however, age was not identified as a predictor for cognitive FGA DT conditions. Similar findings have previously been reported whereby the gait DTC increases more in younger versus older adults for a numeracy DT activity 58 . The authors hypothesised that older adults may have reached their maximal resource capacity with the numeracy task and subsequently showed minimal changes in the gait speed DTC as task difficulty increased from counting backwards in 3's to 7's 58 . It has been shown that compared to younger adults, older persons consume more neural resources to perform simple tasks 58 and are therefore likely to achieve the ceiling effect under high demand conditions 58,59 . We hypothesise that in PwVD the ceiling effect for age was achieved with the FGA in isolation and therefore the further impact of age on numeracy and literacy DT FGA conditions was insignificant.
Sex was a predictive factor for all FGA conditions in PwVD with females having worse FGA single and DT scores. Sex specific gait strategies in response to a physiologic impairment have also been observed. Age-related decreases in saccular function are associated with an increase and decrease in gait speed for men and women, respectively, which may explain the sex impact in all FGA conditions for PwVD 60  www.nature.com/scientificreports/ magnitude and pattern differences in hip, knee and ankle kinematics and kinetics have been reported for healthy women and men, of varying ages, between 20 and 75 years old 61 . The differences in gait kinetics and kinematics were irrespective of age category and the findings suggest that it is important to consider sex-specific analyses in gait studies 62 . It may be that kinematic and kinetic sex-specific differences have a distinct impact on functional gait in PwVD and further work is required to assess the impact of sex on functional single and DT gait in this population.
In healthy participants, sex was a predictive factor for FGA-L with women achieving better FGA scores. Sex specific differences have been reported in healthy adults for verbal fluency tasks that require participants to switch categories, with women performing better than men 60 . The literacy task involved switching between reciting alternate alphabet letters, months or days of the week. Thus, the literacy task may have been easier for healthy women versus men resulting in less DT interference and better FGA scores for the former.
Balance confidence and FGA performance. Balance confidence independently predicted FGA performance, except FGA-N in PwVD. Decreased balance confidence in performing functional activities is associated with actual balance performance in older adults with vestibular dysfunction 63 . Balance confidence contributes to self-efficacy, a person's belief in their ability to succeed in a particular situation 64 . Self-efficacy plays an important role in the effort applied to a task and stress experienced when presented with a challenge 64 . Persons with decreased balance confidence and self-efficacy may modify their behavior to avoid activities and situations that increase symptoms and/or falls risk 64 . PwVD avoid head movement, physical activity, travel, and social commitments to mitigate symptoms 63 . Thus, understanding the relationship between balance confidence with FGA and specific cognitive domains, and addressing this together with self-efficacy should be an important interventional target which may result in improved management.
Self-efficacy has been identified as a mediator of the relationship between cognitive ability and conscientiousness with performance 65 . However, the magnitude of these relationships varies with task complexity. Self-efficacy has been found to mediate the relationships of cognitive ability and conscientiousness with performance on less challenging tasks, but not on more complex tasks 65 . Chen et al. 65 suggest that as tasks become broader and more complex, more generalized, individual, differences influence task performance better than task-specific constructs, such as self-efficacy. This may explain why balance confidence did not predict FGA-N, the most challenging DT condition, in the current study.
Migraine and FGA performance. Migraine independently predicted FGA-N and FGA-L, with the positive β coefficient for migraine (Table 5) suggesting that it is associated with higher (i.e., better) FGA scores. Although cognitive deficits particularly for memory and attention have frequently been reported during the pre-ictal and ictal migraine phase 66,67 , findings during the interictal migraine phase have been divisive 66,68,69 . Factors including migraine frequency, psychological comorbidity, and sample size may account for the heterogeneity of these findings with those experiencing more frequent migraines together with increased psychological symptoms performing worse 67 . A recent study described better performance for visuospatial memory and learning abilities in persons with migraine compared to healthy controls indicating a "cognitive advantage" in those with migraine who have a low frequency of attacks per month 66 , as in our study. Better scores for cognitive task performance have been reported in middle age and older adults with migraine for both global measures of cognition and domain specific findings for executive function and susceptibility to interference 70 . In the present study, none of the persons with migraine history experienced > 3 migraines per month and anxiety and depression symptom scores were within normal levels, which may have contributed to migraine being identified as an independent predictor for FGA-N and FGA-L. However, the sample size for persons with migraine is small and further work is needed to confirm these findings.
The impact of motor, numeracy, and literacy DTs on FGA performance. Average FGA single and DT scores were significantly worse in PwVD compared to healthy participants in our study and to age-range normative values for the FGA single published previously 28 . Cut-off scores for falls risk for the FGA single or DT conditions have not been determined in this population. However, a 20% or greater DTC for gait velocity has a destabilizing effect and increases falls risk 71 . The DTC for FGA-N surpassed this percentage threshold and approached it for FGA-L, suggesting an increased falls risk for these DT conditions compared to FGA single and FGA-M. This finding has potential implications for clinical practice where DT functional gait is often not considered within assessment and intervention programs. Currently, no studies in PwVD have included a pre-post intervention DT gait assessment or investigated the impact of DT training on vestibular rehabilitation outcomes.
DT gait assessment sensitivity depends on the cognitive task used. For both groups, the numeracy and literacy tasks incurred significant DTCs in functional gait compared to the motor task, with the highest sensitivity noted for the numeracy task, as has been reported in persons with MCI 72 and healthy older adults 73 . Literacy (i.e., superior part of Broca's area and premotor cortex) and numeracy task (i.e., temporo-parietal regions) cortical networks are distinct. The numeracy, relative to a literacy task may share more cortical networks with gait, thus producing greater changes in FGA performance 73 . It has been suggested that the left posterior parietal cortex may be involved in sensorimotor integration processes and gait control in real-world conditions 74 , while in older adult females, temporal lobe activation, especially the hippocampus, is associated with gait adaptability during unaccustomed treadmill walking 75 . However, in the current study, although the numeracy task had the highest DTC, no significant differences were noted between FGA-N and FGA-L in the healthy group and the difference between the two was no longer significant in PwVD after Bonferroni correction was applied. The high variability noted for the numeracy and literacy DTCs for both groups, as well as the predominantly younger age for the healthy group, may have contributed to this finding.  14,58,72 . Although, in our study, FGA-N had the highest DTC, a low demand numeracy task (i.e. subtracting from 1) may have shown similar results to FGA single as it is more rhythmic and can cue step pattern 72 . The motor task had the least impact on FGA performance and only a minimal effect on DTC in both groups. Walking while carrying a cup of water has been conceptualized as a single, complex task with one action goal which is to transport the water without any spills 14 . Postural control requirements for gait cannot be dissociated from those for holding a cup of water, as control for transporting a hand-held object while walking is contingent upon the inertial forces created by the gait cycle which act on the object 14 . The cup of water represents an additional postural constraint which increases task complexity but not the number of tasks performed and is therefore insufficient to reveal a DT interference effect 14 . A suitable motor task would be walking while texting on a mobile phone whereby each task goal is separable and can be distinctly measured 14 .
Performance decrements during DT gait are also associated with a person's ability to allocate cognitive resources which depends on cognitive task type and gait task complexity 14 . Task complexity is determined not only by the task's difficulty level but also the performer's expertise and abilities 14 . Thus, a further factor which may have contributed to outcome for all participants was each person's experience with performance of the particular tasks, which was not quantified.
The current study provides insights into the effect of varying task types on FGA performance in PwVD. Further work is needed to determine the optimum task type and content for gait assessment in PwVD. Predictive factors show similarities and differences for DT FGA conditions indicating various DT conditions should be assessed to identify the most appropriate tasks. The proposed DT difficulty framework 76 for persons with MCI can be implemented for PwVD and used to guide clinicians in choosing appropriate tasks to progressively increase cognitive challenge to identify deficits 76 . The poorer performance for specific cognitive domains and their impact on single and DT FGA performance, particularly for FGA-N and FGA-L, indicates a need for cognition and functional gait in combination with a cognitive task to be included within a clinician's assessment in PwVD. In persons who experience dizziness and balance problems following a mild traumatic brain injury, subjective cognitive function scores significantly improve pre-post vestibular rehabilitation, although cognitive symptoms persist 77 . No studies in PwVD have included cognitive function tests pre-post treatment nor is cognition specifically targeted within published vestibular rehabilitation studies. A cognitive and DT FGA assessment may allow for provision of targeted interventions and improved outcomes in future.
Study limitations. Some study limitations are present. Baseline cognitive data was not collected; therefore, DTC on the cognitive task cannot be determined. As secondary task category and content impacts on outcome, future studies in PwVD should investigate the effect of tasks of varying difficulty within categories including auditory tasks. Passive listening to multi-talker babble noise affects FGA performance in young and particularly older adults and those with decreased hearing capacity 19 . Poor sleep quality 78 and low physical activity levels 79 have a detrimental impact on gait; these factors were not included, however, their impact on single and DT FGA should be considered clinically and in future work.

Conclusion
This study provides insights into the effect of chronic vestibular disorders on cognition and DT functional gait. Clinicians should be aware of the additional negative impact of literacy and numeracy tasks on functional gait performance in PwVD. In PwVD, poorer cognitive scores are noted for paired associates learning, reaction time and spatial working memory, irrespective of age, albeit after Bonferroni correction, only the latter remained significant. Gender, varying cognitive domains, balance confidence and migraine history predict FGA single and/or DT performance. The findings support inclusion of a multiple domain cognitive measure and DT FGA that considers various tasks to identify each person's deficits for the provision of targeted interventions towards optimal management and outcome in PwVD.

Data availability
Anonymized data will be available by request from qualified researchers whose data use has been approved by an independent review committee. Initial requests should be addressed to Dr Marousa Pavlou at marousa. pavlou@kcl.ac.uk.